Many proteins interact via two or more contact points that account for the majority of the binding energy between the two. Such a point of interaction may be termed a ‘hot-spot.’ Molecules may be designed having pharmacophores positioned with known separation to interact with these hot-spots. A molecule positioning two pharmacophores for interaction with hot spots may be termed a bivalent molecule. Bivalent compounds may have increased binding energy over similar monovalent compounds, since more than one pharmacophore may interact with the protein. Such compounds may be useful for studying protein-protein interactions, comprise a pharmaceutical lead compounds, or comprise pharmaceuticals.
For protein-protein interactions, studies have shown that amino acid side chain groups or side chains based on amino acid side chain groups contribute a majority of the binding energy, whereas main-chain carbonyl groups contribute relatively little toward the binding energy. Thus, pharmacophores bearing amino acid side chain groups or groups based on amino acid side chain groups are likely to have enhanced binding properties over compounds not having amino acid side chains. Drug leads utilizing unprotected amino acids as pharmacophores are undesirable from both a synthetic and pharmacological standpoint. In response to this need, peptidomimetics have been developed as a means to improve pharmacological properties and lessen synthetic burden. A number of different peptidomimetics have been prepared.
The ability to rapidly prepare libraries of compounds is advantageous for screening of new pharmacophores. Preparation of compound libraries is often achieved by combinatorial methods utilizing solid-phase syntheses. Solution-phase syntheses offer considerable handling advantages over solid-phase methods, but they are usually much slower than solid phase methods for production of compound libraries.
In view of the foregoing, it would be highly beneficial to design peptidomimetics having amino acid side chains or groups based on amino acid side chains, whose structures are amenable to rapid bivalent compound library syntheses by solution phase synthesis methods.